rs201568246

Positions:

• chr14-104703227-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_022489.4(INF2):​c.507+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0014 in 1,613,076 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00090 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0015 (3 hom.)
• Consequence: INF2 NM_022489.4 splice_region, intron
• Scores: Splicing: ADA: 0.00001904
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.565

Genes affected

INF2 (HGNC:23791): (inverted formin 2) This gene represents a member of the formin family of proteins. It is considered a diaphanous formin due to the presence of a diaphanous inhibitory domain located at the N-terminus of the encoded protein. Studies of a similar mouse protein indicate that the protein encoded by this locus may function in polymerization and depolymerization of actin filaments. Mutations at this locus have been associated with focal segmental glomerulosclerosis 5.[provided by RefSeq, Aug 2010]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BP6: Variant 14-104703227-G-A is Benign according to our data. Variant chr14-104703227-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 312678.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000899 (137/152314) while in subpopulation NFE AF= 0.0014 (95/67996). AF 95% confidence interval is 0.00117. There are 0 homozygotes in gnomad4. There are 66 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 137 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INF2	NM_022489.4	c.507+7G>A		splice_region_variant, intron_variant		ENST00000392634.9
INF2	NM_001031714.4	c.507+7G>A		splice_region_variant, intron_variant
INF2	NM_032714.3	c.507+7G>A		splice_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INF2	ENST00000392634.9	c.507+7G>A		splice_region_variant, intron_variant		5	NM_022489.4	P4

Frequencies

GnomAD3 genomes AF: 0.000900 AC: 137 AN: 152196 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00140

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000929 AC: 231 AN: 248558 Hom.: 0 AF XY: 0.000873 AC XY: 118 AN XY: 135220

Gnomad AFR exome AF: 0.000520

Gnomad AMR exome AF: 0.00128

Gnomad ASJ exome AF: 0.000600

Gnomad EAS exome AF: 0.000390

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000186

Gnomad NFE exome AF: 0.00138

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.00145 AC: 2119 AN: 1460762 Hom.: 3 Cov.: 33 AF XY: 0.00138 AC XY: 1004 AN XY: 726722

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.00136

Gnomad4 ASJ exome AF: 0.000766

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000133

Gnomad4 NFE exome AF: 0.00176

Gnomad4 OTH exome AF: 0.00103

GnomAD4 genome AF: 0.000899 AC: 137 AN: 152314 Hom.: 0 Cov.: 34 AF XY: 0.000886 AC XY: 66 AN XY: 74474

Gnomad4 AFR AF: 0.000433

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00140

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00110 Hom.: 0

Bravo AF: 0.00102

EpiCase AF: 0.00142

EpiControl AF: 0.00172

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 26, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	INF2: BP4, BS1 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 30, 2018	- -

Focal segmental glomerulosclerosis 5;C4302667:Charcot-Marie-Tooth disease dominant intermediate E Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 22, 2021	- -

Focal segmental glomerulosclerosis 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.047
DANN	Benign	0.52
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000019
dbscSNV1_RF	Benign	0.10
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs201568246; hg19: chr14-105169564;